Campylobacter jejuni, a NIAID Category B Priority Pathogen, is the leading bacterial cause of human enteritis in the United States and presents a major threat to public health. Increasing resistance of Campylobacter to clinical antibiotics in the past decade raised an urgent demand for the development of alternative intervention strategies, such as vaccination, to prevent and control Campylobacter infections. Despite recent progress on the elucidation of immunogenic and protective antigens in C. jejuni, vaccination of animals against C. jejuni colonization had only partial success and the immunogenic antigens with significant protective effect remain to be determined. The main goal of this R21 application is to develop and evaluate a novel subunit vaccine CmeC against C. jejuni. Outer membrane proteins (OMPs) of C. jejuni are considered the major mediators of the pathogen-host interaction, as a consequence, the promising candidates for the design of protective vaccines. Recently, we have characterized a unique OMP CmeC in Campylobacter. As a key component in multidrug efflux system CmeABC, CmeC contributes Campylobacter resistance to a broad spectrum of antimicrobials and is also essential for Campylobacter colonization in animal intestine by mediating bile resistance. As an immunogenic OMP in vivo, CmeC is widely distributed and constitutively expressed among various Campylobacter strains. Particularly, expression of CmeC is dramatically induced by bile salts present in intestine. Based on these observations, we hypothesize that CmeC is a novel subunit vaccine candidate for immune intervention against Campylobacter infections. To test our hypothesis, we plan to i) examine sequence polymorphism, antigenic homology, and in vitro immune protection of CmeC in primary Campylobacter isolates; ii) evaluate the immunogenicity and protective efficacy of a novel subunit CmeC vaccine in a chicken model of C. jejuni infection; and iii) determine the role of CmeC vaccine in potentiating the efficacy of clinical antibiotics. Once the proposed studies are completed, we expect to obtain critical information on the feasibility of targeting CmeC for immune protection against Campylobacter infections in humans. The unique dual functions of CmeC in intestinal colonization and antibiotic resistance greatly improve innovative aspect and significance of this application. Relevance: Campylobacter jejuni is the most prevalent foodborne bacterial pathogen causing human gastroenteritis in the U.S. The proposed research will provide novel information on the development of effective vaccine against C. jejuni to protect public health. [unreadable] [unreadable] [unreadable]